C1, a highly potent novel curcumin derivative, binds to tubulin, disrupts microtubule network and induces apoptosis

We have synthesized a curcumin derivative, 4-{5-(4-hydroxy-3-methoxy-phenyl)-2-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-3-oxo-penta-1,4-dienyl}-piperidine-1-carboxylic acid tert-butyl ester (C1) that displays much stronger antiproliferative activity against various types of cancer cells including multidrug resistance cells than curcumin. C1 depolymerized both interphase and mitotic microtubules in MCF-7 cells and also inhibited the reassembly of microtubules in these cells. C1 inhibited the polymerization of purified tubulin, disrupted the lattice structure of microtubules and suppressed their GTPase activity in vitro The compound bound to tubulin with a dissociation constant of 2.8±1 μM and perturbed the secondary structures of tubulin. Further, C1 treatment reduced the expression of Bcl2, increased the expression of Bax and down regulated the level of a key regulator of p53, murine double minute 2 (Mdm2) (S166), in MCF-7 cells. C1 appeared to induce p53 mediated apoptosis in MCF-7 cells. Interestingly, C1 showed more stability in aqueous buffer than curcumin. The results together showed that C1 perturbed microtubule network and inhibited cancer cells proliferation more efficiently than curcumin. The strong antiproliferative activity and improved stability of C1 indicated that the compound may have a potential as an anticancer agent.